Abstract

BACKGROUND

Men with multiple comorbidities are often overtreated for low-risk prostate cancer, but it is unclear whether they are undertreated for high-risk cancer, which has appreciable short-term prostate cancer-specific mortality. This study characterized the impact of comorbidity on treatment and survival in men with differing tumor risks.

METHODS

The researchers sampled 1482 men with nonmetastatic prostate cancer at 2 Veterans Affairs hospitals between 1998 and 2004, using multivariate probit regression to determine probabilities of aggressive treatment among men with differing Charlson comorbidity scores within D'Amico tumor risk strata. Using competing-risks regression, a comparison was made of 8-year cancer-specific mortality for men treated aggressively and nonaggressively among Charlson score-tumor risk pairs.

RESULTS

The study sample comprised 516 men (36%) with low-risk, 475 men (33%) with intermediate-risk, and 432 men (30%) with high-risk prostate cancer. Men with high-risk disease tended to have lower probability of aggressive treatment than other risk strata, regardless of comorbidity. Among men with Charlson scores 3+, probabilities of aggressive treatment did not increase with higher tumor risk (0.48, 0.61, 0.49 for low-, intermediate-, and high-risk disease, respectively). In competing-risks analysis, aggressive treatment was not associated with cancer-specific survival benefit in men with multiple comorbidities (Charlson scores of 2 or 3+) and low- and intermediate-risk disease, but there was a strong trend toward survival advantage in such men with high-risk disease.

INTRODUCTION

Thirty years ago, Dr. Willett Whitmore posed the following dilemma regarding treatment of prostate cancer: “When cure is possible, is it necessary? When cure is necessary, is it possible?”[1] Today, with the natural history of prostate cancer and risk stratification models now clearly defined, we are finally beginning to address this dilemma by balancing aggressiveness of treatment with tumor risk: more men with low-risk tumors (and negligible long-term risk of prostate cancer mortality) are treated with active surveillance,[2-4] and men with high-risk tumors (and substantial short-term risk of prostate cancer mortality) are advised to undergo multimodal therapy, for which early results have been favorable.[5-7] However, despite the beginnings of a solution to the Whitmore dilemma with regard to tumor risk, we now are faced with the same quandary regarding comorbidity. For men with multiple comorbidities, we ask: “When they are treated, do they need to be? When they need to be, are they treated?”

Men with multiple comorbidities are often overtreated for low-risk prostate cancer, but rates of undertreatment for men with high-risk disease have yet to be defined. In a recent study, we showed that men with Charlson scores of 3 or greater were aggressively treated with surgery or radiation 55% of the time for low-risk disease, despite an other-cause mortality rate of 70% at 8 years after diagnosis.[8] Although retrospective studies have shown that men with conservatively managed, low-risk prostate cancer have an extremely low likelihood of disease-specific mortality at 10 years (2%-6%),[3, 9] the risk of cancer-specific mortality is substantial in those with high-risk tumors (25%-38%).[9] Therefore, although sicker men clearly do not benefit from aggressive treatment of low-risk disease, it may still be advisable for such men to pursue surgery or radiation therapy for high-risk tumors.

Clinicians may be less likely to offer aggressive treatment to sicker men with high-risk disease for several reasons. First, clinicians may underestimate the cancer-specific mortality risk of high-risk disease over the short term. Second, because sicker men are often poor operative candidates, the scope of treatment for these men is more limited than that of their healthy counterparts. Last, because hormone ablation therapy can halt disease progression over the short-term, clinicians may use it as a backup for localized, high-risk cancer that progresses quickly. However, given the potential cardiac toxicity of androgen deprivation,[10-13] which appears to be especially marked in men with preexisting cardiac disease,[14] this seemingly innocuous treatment paradigm may incur substantial risk for those with multiple comorbidities.

In this study, we sought to characterize the impact of comorbidity on treatment decision-making among groups of men with different tumor risks. We hypothesized that although men with significant comorbidity are overtreated for low-risk disease with aggressive therapies such as surgery or radiation, such men with high-risk disease are being undertreated. Among men with multiple major comorbidities, we hypothesized that there would be a short-term survival advantage with aggressive treatment for men with high-risk disease but not for those with low- and intermediate-risk disease.

MATERIALS AND METHODS

Data Sources and Study Participants

We used the California Cancer Registry to identify all men newly diagnosed with prostate cancer at the Greater Los Angeles and Long Beach Veterans Affairs Medical Centers, in California, between 1997 and 2004. We reviewed medical records to determine age, race, tumor characteristics, type of primary treatment, comorbidities at diagnosis, as well as date and cause of death. For this study, we included all men with a new diagnosis of prostate cancer. We excluded men with metastatic disease at diagnosis, prostate cancer diagnosed incidentally at the time of cystoprostatectomy, and those with insufficient data to determine comorbidities or treatment type. After reviewing 1915 new cases, we identified 1482 men who satisfied the inclusion and exclusion criteria. Institutional Review Board approval was granted at University of California Los Angeles and both VA Hospitals.

Variables

Comorbidity

We assessed comorbidity using the age-unadjusted Charlson comorbidity index.[15] The Charlson index estimates life expectancy based on the presence or absence of specific comorbidities; each comorbidity is weighted by its risk of mortality, and these weights are summed into a total score that is proportional to an individual's overall mortality risk. Comorbidities are weighted as follows: Metastatic solid tumor (6), HIV/AIDS (6), moderate-to-severe liver disease (3), hemiplegia (2), moderate-to-severe renal disease (2), diabetes with end-organ damage (2), any solid tumor (2), leukemia/lymphoma (2), myocardial infarction (1), congestive heart failure (1), peripheral vascular disease (1), cerebrovascular disease (1), dementia (1), chronic pulmonary disease (1), connective tissue disease (1), peptic ulcer disease (1), mild liver disease (1), and diabetes (1). Prostate cancer was not included in Charlson comorbidity scoring, either as “any solid tumor” or “metastatic solid tumor”. We collected comorbidities at the time of diagnosis by review of the interdisciplinary medical record within 12 months of diagnosis. Comorbidities had to have been present at the time of treatment decision. We divided men into 4 groups: Charlson scores 0, 1, 2, and 3+.

Tumor Risk

Tumors were risk-stratified using the widely accepted D'Amico risk criteria, which use prostate-specific antigen (PSA), Gleason sum, and clinical stage at diagnosis to predict risk of progression, overall mortality, and cancer-specific mortality. Tumors are classified as low-, intermediate-, or high-risk.[16, 17]

Type of Primary Treatment

Type of primary treatment was likewise determined from the medical record. Aggressive treatment was defined as radical prostatectomy, radiation therapy (with or without androgen deprivation therapy [ADT]), and brachytherapy. Immediate or delayed ADT or watchful waiting were considered to be nonaggressive treatment.

Mortality

Survival was measured from date of treatment until date of death. We determined date of death using a combination of the medical record and the Social Security Death Index. Cause of death was determined using the medical record by the following algorithm. Men were considered to have died from prostate cancer based on: enrollment in hospice or palliative care for prostate cancer, advancing PSA despite secondary hormonal therapy or chemotherapy, or death as a sequela of metastatic disease (bony fracture or organ failure related to metastasis). Non–prostate cancer mortality was defined as death from other causes as noted in the medical record. If cause of death could not be determined from the medical record, subjects were considered to have died from other causes if: PSA was stable 5 years after local treatment, PSA was stable 1 year prior to death after local treatment for D'Amico intermediate/high- and 2 years prior to death for low-risk disease, PSA was stable 6 months prior to death while on hormonal therapy for locally advanced or recurrent disease, or if primary or secondary hormonal therapy was not initiated within 6 months prior to death for locally advanced or recurrent disease.

Statistical Analysis

We first compared clinical and demographic characteristics among Charlson comorbidity index score groups using chi-square and Fisher's exact tests. After dividing our group by tumor risk and comorbidity, we used survival analysis to tabulate 8-year cumulative other-cause and prostate cancer–specific mortality. We then used a multivariate Cox proportional hazards model to obtain hazard ratios for other-cause mortality. The competing-risks regression model was corrected for age, race, site, and type of treatment (aggressive versus nonaggressive; other covariates were categorical as listed in Table 1).

We used a multivariate probit model to determine the probabilities of receiving aggressive treatment among Charlson comorbidity and D'Amico tumor risk pairs. We generated 95% confidence intervals (CIs) around the predicted probabilities using bias-corrected bootstrapping with 1000 repetitions. Estimates were corrected for age, race, and site (covariates were categorical as listed in Table 1).

To determine the potential benefit of aggressive over conservative treatment, we compared cancer-specific survival between aggressively and conservatively treated men for each tumor-risk/comorbidity pair using competing-risks regression analyses.[18] Models were corrected for age (< 66/66-76/> 76), race (Caucasian versus other), and site (West Los Angeles, Calif, versus Long Beach, Calif). For this analysis, we used multiple imputation to estimate missing values for race, using a logit model containing all covariates. We used P < .05 to denote statistical significance, and all tests were 2-sided. All statistical analyses were performed in SAS version 9.2 (SAS Institute, Cary, NC) or Stata version 11.0 (Stata, College Station, Tex).

RESULTS

Table 1 shows the characteristics of our sample. Men with higher Charlson comorbidity scores were older and had higher Gleason scores. They were treated more often with radiation and watchful waiting and less often with surgery. D'Amico tumor risk was evenly split in our sample and equally distributed among Charlson groups; in the overall sample, 516 men (36%) had low-risk, 475 men (33%) had intermediate-risk, and 432 men (30%) had high-risk prostate cancer.

Cumulative nonprostate and prostate cancer–specific mortality by Charlson score and D'Amico tumor risk, as well as hazard ratios for non–prostate cancer mortality, are listed in Table 2. As expected, higher Charlson scores were associated with higher other-cause mortality in all tumor risk groups. Men with Charlson scores of 3 or greater with low-, intermediate-, and high-risk tumors had 8-year other-cause cumulative mortality estimates of 45%, 85%, and 80%, respectively. In the competing-risks regression model, the hazard ratios for other-cause mortality for men with Charlson scores of 3 or greater in the low-, intermediate-, and high-risk tumor groups were 6.2 (95% CI = 3.4-11.1), 7.5 (95% CI = 6.2-18.0), and 10.5 (95% CI = 4.8-11.7), respectively. Eight-year cumulative prostate cancer mortality was 0.4%, 3%, and 8% among low-, intermediate-, and high-risk tumor groups, respectively.

Multivariate probabilities of receiving aggressive treatment by D'Amico tumor risk and Charlson comorbidity score are presented in Figure 1. Men with high-risk disease tended to have a lower probability of aggressive treatment than other risk strata, regardless of comorbidity score. Among men with Charlson scores of 3 or greater, probabilities of aggressive treatment did not increase with higher tumor risk (0.48, 0.61, 0.49 for low-, intermediate-, and high-risk disease, respectively). As Charlson comorbidity score increased, there was a slight overall downtrend in probability of aggressive treatment for men with low- and intermediate-risk disease, but men with the highest Charlson scores still had relatively high probabilities of aggressive treatment for low- and intermediate-risk disease (range, 0.48-0.61).

Prostate cancer–specific mortality among men receiving aggressive and nonaggressive treatment by Charlson score/tumor risk subgroups is shown in Figure 2 and Table 3. For men with multiple major comorbidities (Charlson score of 2 or greater), aggressive treatment was not associated with a significant survival advantage in low- and intermediate-risk subgroups, but men treated aggressively for high-risk disease tended to have lower cancer-specific mortality compared with those treated conservatively (P = .06). Among men with 1 or fewer major comorbidities (Charlson score of 1 or less), aggressive treatment was associated with a significant survival advantage only in those with intermediate- or high-risk disease. Overall, among men treated conservatively, the absolute risk of 8-year prostate cancer mortality was appreciable in those with high-risk disease (5%-27%) but was noticeably less in those with intermediate- (1%-7%) and low-risk disease (0%-1%).

Figure 2. Prostate cancer–specific mortality is shown in men treated with aggressive and nonaggressive therapy by tumor risk and Charlson score. P values represent competing-risks regression analysis comparisons between men treated aggressively and nonaggressively within comorbidity/tumor risk pairs (Charlson groups pooled by 0-1 and 2-3+), corrected for age, race, site, and race. Asterisk (*) indicates model did not run due to no events in either group.

DISCUSSION

At the outset of this study, we posed the following question regarding treatment choice for men with early-stage prostate cancer and multiple comorbidities: When they are treated, do they need to be? When they need to be, are they treated? The data presented in this study suggest that the answers are the opposite of what one would hope them to be. Men with multiple major comorbidities are not only being overtreated for low- and intermediate-risk disease, for which there was no significant benefit to treatment over 8 years, but are also being undertreated for high-risk disease, for which there was an apparent benefit to treatment. We showed that although men with high-risk disease were the least likely to be treated aggressively for any given Charlson score, they were more likely to derive a cancer-specific survival benefit with aggressive treatment. Conversely, whereas men with low- and intermediate-risk disease and multiple comorbidities were more likely to be treated aggressively, they did not have any significant survival benefit with aggressive treatment.

Because older men with multiple major comorbidities are unlikely to survive longer than 10 years,[19-22] our short-term estimates of treatment benefit are the final endpoint for the majority of these men. If there is truly no short-term cancer-specific survival benefit with aggressive treatment of men with low- and intermediate-risk disease, we are committing the majority of them to significant morbidities, such as impotence, incontinence, and bowel dysfunction,[23] for example, in exchange for a treatment that has no benefit. Likewise, if there is an apparent short-term survival benefit with aggressive treatment of men with high-risk disease, we can be more confident about the value of aggressive treatment in this setting, because at least it serves some useful purpose.

Extant literature supports aggressive local treatment of high-risk disease for prevention of cancer-specific mortality within 10 years of diagnosis. In a large retrospective study of men with conservatively managed, clinically localized prostate cancer, those with poorly differentiated (Gleason score of 8 or higher) disease had much higher 10-year cancer-specific mortality (25%-38%) than those with moderately differentiated (Gleason score of 5-7) disease (6%).[9] Aggressive treatment of high-risk disease with multimodal therapy, namely, surgery as primary local treatment with subsequent selective use of radiation and hormonal therapy, appears to substantially decrease 10-year cancer-specific mortality, with estimates ranging from 8% to 13% in institutional case series.[24-26] Direct comparisons of aggressive versus conservative management in observational cohorts have corroborated the benefits of aggressive therapy for high-risk disease at early endpoints; in a recent study comparing 10-year cancer-specific survival among men treated with upfront surgery, radiation therapy, or watchful waiting in the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) trial, men with CAPRA scores of 8 to 10 showed a consistent, marked improvement with primary surgical therapy over radiation therapy or watchful waiting, after correction for age, race, and comorbidity.[27] Comparing these considerable survival benefits with the paltry ones observed at 10 years with aggressive treatment of low- and intermediate-risk disease (3%-6% absolute risk reduction)[28, 29] supports our idea that rates of aggressive treatment should be higher for men with high-risk disease, even in men with limited life expectancy.

Although it may seem rational to use conservative management in all men with multiple major comorbidities, our data argue for a more individualized approach to patient care. We do not believe in rationing of care for men with multiple comorbidities, but rather that care should be rational: that men should be treated only for disease that poses a real threat to their remaining years. Ideally, this would mean screening men with multiple major comorbidities within the current American Urological Association guidelines as usual, but reserving aggressive treatment only for those with high-risk disease.

Of course, no parameter can substitute for the clinical judgment of the physician; some patients may be unusually sick or healthy for their comorbidity status and therefore fall outside of the typical treatment paradigm. Furthermore, the patient's individual preferences should always be considered. Although we believe that most older men with multiple comorbidities should be treated conservatively for low-/intermediate-risk disease and aggressively for high-risk disease, these decisions must be individualized. As such, it is difficult to determine what the “appropriate” rate of aggressive treatment should be for these men. Regardless, we feel that these individual decisions should be informed by a realistic understanding of the likelihood of treatment benefit and morbidity.

This retrospective cohort study should be interpreted in the context of several limitations. First, because treatment selection was not randomized, selection bias for healthier patients in the group treated aggressively may bias toward earlier other-cause mortality in the group treated conservatively. By reflexively lowering the risk of prostate cancer mortality in the conservatively managed group, this bias would make it easier to prove that men with low- and intermediate-risk disease do not benefit from aggressive treatment but harder to prove that men with high-risk disease do benefit from aggressive treatment. Second, because comorbidity status was collected retrospectively from the medical record, sicker men may have proportionally more comorbidities recorded than would healthier men, due to a greater number of medical visits. Finally, because prostate cancer mortality is a rare event, we were not able to definitively rule out the possibility that the observed treatment benefit in men with multiple comorbidities and high-risk disease was due to chance (P = .06). However, given our a priori hypotheses, we feel that this was due to lack of power, not to a lack of treatment effect. Our findings will need to be repeated in a larger population.

In conclusion, we show that aggressiveness of treatment is poorly matched with tumor risk in men with severe comorbidity. Although men with multiple major comorbidities were often treated aggressively for low- and intermediate-risk disease, for which there was no apparent survival benefit, they were less often treated aggressively for high-risk disease, for which there was a clear trend toward survival benefit. We believe that men with multiple major comorbidities should strongly consider conservative management of low- and intermediate-risk disease and aggressive treatment of high-risk disease. We will then be able to say, “When these men are treated, they need to be, and when they need to be, they are treated.”